Ipsen (Euronext: IPN; ADR: IPSEY) today announced that the Committee for
Medicinal Products for Human Use (CHMP), the scientific committee of the
European Medicines Agency (EMA), has adopted a positive opinion
recommending the approval of Xermelo® (telotristat ethyl) 250
mg three times a day (tid) for the treatment of carcinoid syndrome
diarrhea in combination with somatostatin analogue (SSA) therapy in
adults inadequately controlled by SSA therapy. The CHMP positive opinion
will now be reviewed by the European Commission (EC), which has the
authority to approve medicines for use in the 28 countries of the
European Union, as well as Norway, Liechtenstein and Iceland.

David Meek, Chief Executive Officer of Ipsen, said: “The
positive CHMP opinion for Xermelo® is an
important milestone towards providing innovative solutions along every
step of the treatment pathway for neuroendocrine tumors. Xermelo®
is a novel treatment option and is the first oral tryptophan hydroxylase
inhibitor, studied in combination with a somatostatin analog to
demonstrate significant relief to patients and can contribute to an
improved quality of life. We are very pleased to move closer to
providing a new treatment option for European patients suffering from
this debilitating condition.”

“The medical community is very pleased to have Xermelo®
as a new therapeutic option for patients with carcinoid syndrome”, said
Professor Juan Valle, University of Manchester andThe
Christie in Manchester, UK. He added “The positive safety and
efficacy data of telotristat ethyl has meant that it has already been
integrated in the majority of international guidelines including ENETS1
guidelines reflecting the high level of unmet need in this condition”.

The detailed recommendations for the use of this product will be
described in the Summary of Product Characteristics (SmPC), to be made
available once the medication receives marketing authorization from the
European Commission.

About the TELESTAR Phase 3 Pivotal Trial
The efficacy and
safety of telotristat ethyl 250 mg taken tid were established in a
12-week double-blind, placebo-controlled, randomised, multicentre phase
3 trial. The study included a 36-week open-label extension period during
which all patients were treated with a higher dose of telotristat ethyl.
A total of 135 patients were recruited in 12 countries (AU, BE, CA, FR,
DE, IL, IT, NL, ES, SE, UK, USA). The mean age was 64 years (range 37 to
88 years) and 52% were male. All patients had a well-differentiated
metastatic neuroendocrine tumours with documented history of carcinoid
syndrome, and were treated with stable-dose SSAs for ≥ 3 months before
enrolment. Patients had an average of four or more bowel movements (BM)
per day: at baseline, mean daily BM frequency averaged over the baseline
period were 5.2 and 6.1 counts/day in the placebo and telotristat ethyl
250 mg groups, respectively. The study included a 12-week double-blind
treatment (DBT) period, in which patients initially received placebo
(n=45) or telotristat ethyl 250 mg (n=45) or a higher dose (telotristat
ethyl 500 mg; n=45) three times daily. During the study, patients were
allowed to use rescue medication (short-acting SSA therapy) and
anti-diarrheals for symptomatic relief but were required to be on
stable-dose of long-acting SSA therapy for the duration of the DBT
period.

The primary endpoint was the mean change from baseline in daily BM
frequency averaged over the 12-week double blind period. Estimated
difference in BM frequency per day versus placebo averaged over 12 weeks
was -0.81 for telotristat ethyl 250mg (p<0.001).

A substantially greater proportion of patients on telotristat ethyl 250
mg tid achieved a durable response, defined as at least a 30 percent
reduction in daily bowel movements over at least half the days of the
12-week DBT period: 44 percent on telotristat ethyl, as compared to 20
percent on placebo (p<0.040). When the full effect of telotristat ethyl
is observed (during the last 6 weeks of the DBT period) the proportion
of responders with at least 30% BM reduction was 51% (23/45) in the 250
mg group versus 22% (10/45) in the placebo group (post-hoc
analysis).

About the TELECAST Phase 3 Trial
The Phase 3 TELECAST study
was designed similarly to TELESTAR study as a companion to this pivotal
Phase 3 study to provide additional efficacy and safety information in
patients with carcinoid syndrome.
A total of 76 patients were
evaluated for efficacy. The mean age was 63 years (range 35 to 84 years)
and 55% were male. All patients had well-differentiated metastatic
neuroendocrine tumour with carcinoid syndrome. Most patients (92.1%) had
fewer than 4 BM per day and all except 9 were treated by SSA therapy.

The primary endpoints were the percent change from Baseline in u5-HIAA
at Week 12 and incidence of treatment emergent adverse events (TEAEs).
The mean u5-HIAA excretion at baseline was 69.1 mg/24hours in the
telotristat ethyl 250 mg tid group (n=17) and 84.8 mg/24hours in the
placebo group (n=22). The percent change from baseline in u5-HIAA
excretion at week 12 was +97.7% in the placebo group versus -33.2% in
the telotristat ethyl 250 mg tid group.

Notably, 40% of patients in the telotristat ethyl 250 mg tid treatment
arm achieved a ≥30% reduction in BM frequency for at least 50% of the
days in the double-blind treatment period, while there were no
responders in the placebo arm (p=0.001).

General safety information about Xermelo®
In
clinical trials, over 230 patients with carcinoid syndrome were treated
with Xermelo®. The placebo-controlled safety analyses were
focused on the integrated data from the 12-week placebo-controlled
double-blind periods from the two phase 3 randomized clinical trials.
For this safety analysis, 71 patients received placebo and 70 patients
received Xermelo® 250 mg three times daily. The most commonly
reported adverse reactions in patients treated with telotristat ethyl
were abdominal pain (26%), gamma-glutamyl transferase increased (11%)
and fatigue (10%). They were generally of mild or moderate intensity.
The most frequently reported adverse reaction leading to discontinuation
of telotristat ethyl was abdominal pain in 7.1% of patients (5/70).

About carcinoid syndrome (CS)
Well-differentiated
neuroendocrine tumor (NET) is a relatively rare tumor type that arises
from cells of the neuroendocrine system. Carcinoid syndrome (CS) occurs
when well-differentiated NETs secrete large amounts of serotonin and
other vasoactive products into the systemic circulation. Classically,
symptoms associated with CS include cutaneous flushing, diarrhea,
wheezing, abdominal pain, and in the long-term, valvular heart disease.

Somatostatin analogues (SSA) are the cornerstone of therapy for the
relief of CS and tumor control. SSA inhibit the release of serotonin by
NETs and have become first-line therapy for CS.
Due to the severe
morbidity of CS and the lack of established treatment options, the
population of patients with CS needing further control in addition to
their SSA therapy is one with a high unmet medical need.

About Xermelo® (telotristat ethyl)
Xermelo®
is a novel, orally administered, inhibitor of the enzyme tryptophan
hydroxylase (TPH). Through inhibition of TPH, the rate-limiting step in
the synthesis of serotonin, Xermelo® was designed to reduce
the production of serotonin within neuroendocrine tumors.

On 22 October 2014, Ipsen and Lexicon announced that they had entered
into an exclusive licensing agreement for Ipsen to commercialize Xermelo®
(telotristat ethyl) in all territories excluding the United States and
Japan, where Lexicon retains the rights. On 28 February 2017, Lexicon
received U.S. Food and Drug Administration (FDA) approval for Xermelo®
as a first and only orally administered therapy for the treatment of
carcinoid syndrome diarrhea in combination with somatostatin analog
(SSA) therapy in adults inadequately controlled by SSA therapy.

About Ipsen
Ipsen is a global specialty-driven
biopharmaceutical group focused on innovation and specialty care. The
group develops and commercializes innovative medicines in three key
therapeutic areas - Oncology, Neurosciences and Rare Diseases. Its
commitment to oncology is exemplified through its growing portfolio of
key therapies for prostate cancer, neuroendocrine tumors, renal cell
carcinoma and pancreatic cancer. Ipsen also has a well-established
Consumer Healthcare business. With total sales close to €1.6 billion in
2016, Ipsen sells more than 20 drugs in over 115 countries, with a
direct commercial presence in more than 30 countries. Ipsen's R&D is
focused on its innovative and differentiated technological platforms
located in the heart of the leading biotechnological and life sciences
hubs (Paris-Saclay, France; Oxford, UK; Cambridge, US). The Group has
about 5,100 employees worldwide. Ipsen is listed in Paris (Euronext:
IPN) and in the United States through a Sponsored Level I American
Depositary Receipt program (ADR: IPSEY). For more information on Ipsen,
visit www.ipsen.com.

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